New treatment options and challenges for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer with brain metastases

Up to a third of patients with non-small cell lung cancer (NSCLC) may develop brain metastases, typically portending a poor prognosis (1). Data suggest that median overall survival (OS) for patients who develop brain metastases after diagnosis is 10 months, and even shorter for patients who present with brain metastases at time of diagnosis (as low as 5 months) (2). Patients whose tumors harbor anaplastic lymphoma kinase (ALK) rearrangements have been observed to have longer median OS than patients with wild-type tumors, with one study reporting a 49-month median OS after development of brain metastases. However survival for patients who develop central nervous system (CNS) metastases while on crizotinib therapy has been reported as significantly shorter (10 months) (3). Treatment options for patients with progressive CNS disease include whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or a combination of these local modalities. Recent data suggest patients experience less neurocognitive toxicity from SRS alone if treating 1–3 brain metastases (4), and patients with lung cancer seem to do better with SRS than with WBRT, although this is likely due in part to selection of patients with multiple lesions for WBRT rather than SRS (5).

The initial studies and subsequent FDA approval of crizotinib, the first ALK inhibitor (6,7), yielded impressive initial clinical responses but resistance inevitably develops and patients ultimately experience disease progression. In a pooled analysis of two landmark trials, disease progression occurred in the CNS in 72% of patients (8). Acquired resistance to crizotinib has been observed to occur through a variety of mechanisms including ALK dependent mechanisms (ALK amplification, secondary ALK mutations), and “bypass tracks” such as increased EGFR phosphorylation and KRAS mutations (9-11). Progression within the CNS may occur because of inadequate penetration of crizotinib in the CSF (12), although recent data with alectinib suggest that CSF concentrations are not predictive of efficacy (13).

Resistance to crizotinib has led to the development of next-generation ALK-inhibitors, including ceritinib and alectinib. In a dose-finding phase I study, alectinib demonstrated impressive activity with 55% of patients experiencing a response, and 52% of patients with brain metastases experienced a response in the CNS (14). Gadgeel et al. (15) pooled data from two single-arm phase II trials, NP28673 and NP 28671, including 136 patients with baseline CNS disease prior to initiation of alectinib (of 225 total patients) representing 60% of the total study population in the two trials. The primary endpoint of both studies was objective response rate (ORR) by independent review committee. Trial NP28673, which included 138 patients from 16 countries, demonstrated an ORR of 50%, and 61% of all patients had CNS disease at baseline. CNS ORR was 57% among the 35 patients with measurable CNS disease at baseline. Trial NP28671 evaluated 87 patients and found a similar ORR of 48%, however the CNS ORR was 75%. In the 18 patients with CNS disease at baseline who had not received prior radiation therapy, responses were seen in 67%, included ten complete responses. In both trials, patients with symptomatic CNS disease were excluded. In the pooled analysis, after a median follow-up of 12.4 months, alectinib demonstrated impressive efficacy in patients with measurable CNS disease at baseline, with 64% of patients achieving an objective response including 22% who achieved complete response. The ORR for patients with non-measurable CNS disease at baseline was somewhat lower at 43%, but complete response rate was higher (27%). Response rates were higher in patients how had not received prior radiation therapy, and were higher in patients whose radiation took place greater than 6 months prior to initiation of alectinib treatment. CNS ORR in patients who had not received prior radiation was 58.5% compared to 35.8% for those patients who had received radiation, and included a higher rate of complete responses (49% vs. 18%). Significantly, unlike prior studies of ALK inhibitors where the CNS was the most common site of disease progression, only 17% of patients in these two trials had progression in the CNS. Promisingly, among patients without CNS disease at baseline only 8% developed CNS disease during treatment.

Gadgeel and colleagues are to be congratulated on their work and the implications for clinical practice. The study raises several interesting questions which will be pivotal to answer in order to make the best decisions for our patients. It would be interesting to know what type of prior radiation therapy the patients had received, whether WBRT or SRS or both, to see if response and duration of efficacy vary by prior treatment. This important question should be addressed in future prospective trials. Additionally it would be informative to know how many CNS lesions patients had, as patients with multiple lesions are more likely to undergo WBRT rather than SRS (16), although ALK-positive patients treated with crizotinib have favorable outcomes when treated with SRS for both oligometastases (≤5 CNS lesions) and polymetastases (>5) (17).

In both trials, patients were ineligible if they had received an ALK-inhibitor other than crizotinib. The question of how patients treated with ceritinib after progressing on crizotinib will respond within the CNS has yet to be addressed. Ceritinib has shown activity within the CNS, with a CNS ORR of 37.7% demonstrated in pooled analysis of the ASCEND-1 and -2 trials, including a 45% response rate in the heavily-pretreated ASCEND-2 study population (18). Table 1 shows the results of two pooled evaluations of CNS efficacy of ceritinib and alectinib, respectively, although the study populations vary significantly and direct comparison is not possible.

Table 1 Pooled analyses of CNS activity of ceritinib and alectinib in ALK-positive NSCLC
Full table

Finally, data on the subsequent treatment would be useful for the 17% of patients that developed progression in the CNS while on therapy with alectinib. The concept of “treatment beyond progression” for oligometastatic CNS disease who receive SRS to progressing lesions has been well established for patients receiving crizotinib therapy (16,17,19), and could inform decision making for patients on alectinib. More data on the treatment of these patients will be forthcoming as more patients are treated with alectinib either in the clinical trials setting or as a part of standard of care.

The addition of alectinib to the treatment portfolio in ALK-positive patients and the current study by Gadgeel et al. raise several interesting clinical scenarios. Medical oncologists must assess each patient’s unique situation in conjunction with a multi-disciplinary team including radiation oncologists, neuro-oncologists, and neuro-surgeons, and utilize all available data to make the best-informed evidence-based decisions for their patients. The question of whether up-front alectinib is superior to crizotinib will be answered by the ongoing ALEX and J-ALEX trials, with early results from the Japanese population studied in the J-ALEX study suggesting better outcomes for patients treated with alectinib (20). Until the final data are available, however, the clinical question will arise commonly among patients progressing on crizotinib or ceritinib.

Our current practice is to avoid WBRT whenever possible for patients with asymptomatic CNS progression on ALK-directed therapy in order to avoid or minimize neurotoxicity, especially in patients who are young with excellent anticipated survival. Enrollment on a clinical trial is preferred. For patients not suitable to trial or for whom trials are not readily available, in the setting of good systemic control but isolated or oligometastatic CNS progression, treating with SRS while continuing either crizotinib or ceritinib is a reasonable approach and supported in the literature (17,19). This allows for maximal duration of systemic clinical benefit with crizotinib. In the setting of good systemic control but multiple CNS lesions where SRS is not felt to be feasible, switching to alectinib is indicated as supported by the current work by Gadgeel et al. For patients who present with CNS disease at baseline, then initiation of an agent with good CNS efficacy such as alectinib would be optimal.

These encouraging results broaden the therapeutic options for clinicians and patients with ALK-positive NSCLC. Further clinical trials will help address outstanding questions. As more data become available on additional ALK-inhibitors such as brigatinib and lorlatinib, the question will be of the optimal sequencing of therapies, especially since early reports demonstrate CNS activity with these agents as well (21). Also, the choice of SRS, alectinib, or both has yet to be delineated in prospective trials. In patients harboring an EGFR mutation, the addition of TKI therapy to SRS or WBRT has so far met with mixed results (22-24). The possibility of treating with alectinib first and using SRS for lesions that persist after therapy remains an option that has not been tested. Patients who are symptomatic from their CNS disease represent the entirely separate cohorts who require immediate treatment. Efficacy of alectinib in these patients has not yet been reliably evaluated. Also, the incidence of “pseudo-progression” due to radiation necrosis in patients treated with alectinib (25), as well as the optimal strategy to identify and manage these patients remains unclear.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Sørensen JB, Hansen HH, Hansen M, et al. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988;6:1474-80. [Crossref] [PubMed]
2. Ali A, Goffin JR, Arnold A, et al. Treatment and outcome of patients with brain metastases from non-small cell lung cancer (NSCLC). J Clin Oncol 2009;27:abstr e19058.
3. Xing P, Wang S, Hao X, et al. Clinical data from the real world: efficacy of Crizotinib in Chinese patients with advanced ALK-rearranged non-small cell lung cancer and brain metastases. Oncotarget 2016;7:84666-84674. [PubMed]
4. Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016;316:401-9. [Crossref] [PubMed]
5. Kim K, Lee J, Chang M, et al. Primary chemotherapy, stereotactic radiosurgery, or whole brain radiotherapy in non-small cell lung cancer (NSCLC) patients with asymptomatic brain metastases. J Clin Oncol 2009;27:abstr e19063.
6. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703. [Crossref] [PubMed]
7. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011-9. [Crossref] [PubMed]
8. Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015;33:1881-8. [Crossref] [PubMed]
9. Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012;18:1472-82. [Crossref] [PubMed]
10. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. [Crossref] [PubMed]
11. Lovly CM, Shaw AT. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res 2014;20:2249-56. [Crossref] [PubMed]
12. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443-5. [Crossref] [PubMed]
13. Metro G, Lunardi G, Bennati C, et al. Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series. J Neurooncol 2016;129:355-61. [Crossref] [PubMed]
14. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119-28. [Crossref] [PubMed]
15. Gadgeel SM, Shaw AT, Govindan R, et al. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34:4079-85. [PubMed]
16. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14. [Crossref] [PubMed]
17. Choi JW, Kong DS, Seol HJ, et al. Outcomes of Gamma Knife Radiosurgery in Combination with Crizotinib for Patients with Brain Metastasis from Non-Small Cell Lung Cancer. World Neurosurg 2016;95:399-405. [Crossref] [PubMed]
18. Felip E, Crinò L, Kim DW, et al. 141PD: Whole body and intracranial efficacy of ceritinib in patients (pts) with crizotinib (CRZ) pretreated, ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) and baseline brain metastases (BM): Results from ASCEND-1 and ASCEND-2 trials. J Thorac Oncol 2016;11:S118-9. [Crossref] [PubMed]
19. Takeda M, Okamoto I, Nakagawa K. Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement. J Thorac Oncol 2013;8:654-7. [Crossref] [PubMed]
20. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. J Clin Oncol 2016;34:abstr 9008.
21. Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol 2016;17:1683-96. [Crossref] [PubMed]
22. Cai L, Qiu X, Yang H, et al. Evaluation on efficacy and safety of the addition of X-knife therapy to gefitinib in NSCLC patients with symptomatic brain metastases. Oncotarget 2016. [Epub ahead of print]. [PubMed]
23. Cai L, Zhu JF, Zhang XW, et al. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer. J Neurooncol 2014;120:423-30. [Crossref] [PubMed]
24. Byeon S, Ham JS, Sun JM, et al. Analysis of the benefit of sequential cranial radiotherapy in patients with EGFR mutant non-small cell lung cancer and brain metastasis. Med Oncol 2016;33:97. [Crossref] [PubMed]
25. Ou SH, Klempner SJ, Azada MC, et al. Radiation necrosis presenting as pseudoprogression (PsP) during alectinib treatment of previously radiated brain metastases in ALK-positive NSCLC: Implications for disease assessment and management. Lung Cancer 2015;88:355-9. [Crossref] [PubMed]